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Abstract：
Trimethyltin chloride (TMT) is a by-product in the synthesis of organotin, a plastic stabilizer. With the rapid development of industry, the occupational hazards caused by TMT cannot be ignored. TMT is a typical neurotoxicant, which mainly damages the limbic system and brainstem of the nervous system. Previous studies have demonstrated that the neurotoxicity induced by TMT is linked to the inhibition of energy metabolism, but the underlying mechanism remains elusive. In order to investigate the mechanism of TMT-induced inhibition of energy metabolism, C57BL/6 male mice were administered by IP injection in different TMT doses (0 mg/kg, 1.00 mg/kg, 2.15 mg/kg and 4.64 mg/kg) and times (1d, 3d and 6d), and then the changes of superoxide dismutase (SOD) activity, malondialdehyde (MDA) level and Na+-K+-ATPase activity in cerebral cortex, cerebellum, hippocampus, pons, medulla oblongata of mice, the expressions of Na+-K+-ATPase protein, AMP-activated protein kinase (AMPK), phosphorylated AMP-activated protein kinase(p-AMPK)and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) in hippocampus and medulla oblongata were measured; the effects of TMT on the viability, the activity of SOD, glutathione (GSH) and Na+-K+-ATPase, MDA level, and the expression of PGC-1α and Na+-K+-ATPase protein in N2a cells were measured by different TMT doses and times, in order to verify the experiments in vivo. Our results found that most of the mice showed depression, tremor, epilepsy, spasm and other symptoms after TMT exposure. Moreover, with the increase of TMT dose, the activity of Na+-K+-ATPase and the expressions of AMPK protein in the hippocampus and medulla oblongata of mice decreased, and the expressions of p-AMPK protein increased. Peroxidative damage was evident in hippocampus, medulla oblongata of mice and N2a cells, and the expression of PGC-1α and Na+-K+-ATPase protein was significantly down-regulated. Therefore, it is reasonable to believe that TMT-induced neurotoxic symptoms and inhibition of energy metabolism may be related to p-AMPK and down-regulation of PGC-1α in the hippocampus and medulla oblongata.
摘要：
三甲基氯化锡(TMT)是有机锡合成中的副产品,塑料稳定剂。随着工业的快速发展,TMT带来的职业病危害不容忽视。TMT是一种典型的神经毒物,主要损害边缘系统和神经系统的脑干。先前的研究表明，TMT引起的神经毒性与抑制能量代谢有关，但是潜在的机制仍然难以捉摸。为了探讨TMT抑制能量代谢的机制,C57BL/6雄性小鼠以不同的TMT剂量（0mg/kg，1.00mg/kg,2.15mg/kg和4.64mg/kg）和次（1d，3d和6d)，超氧化物歧化酶(SOD)活性的变化,大脑皮层丙二醛(MDA)水平和Na+-K+-ATP酶活性,小脑,海马体,pons,小鼠延髓，Na+-K+-ATP酶蛋白的表达,AMP激活蛋白激酶(AMPK),测量海马和延髓中磷酸化的AMP激活的蛋白激酶（p-AMPK）和过氧化物酶体增殖物激活的受体γ-共激活因子-1α（PGC-1α）；TMT对生活力的影响，SOD的活性，谷胱甘肽（GSH）和Na+-K+-ATP酶，MDA水平,用不同剂量和时间的TMT检测N2a细胞中PGC-1α和Na+-K+-ATPase蛋白的表达,为了验证实验在体内。我们的结果发现，大多数小鼠表现出抑郁症，震颤,癫痫,TMT暴露后出现痉挛等症状。此外，随着TMT剂量的增加,小鼠海马和延髓Na+-K+-ATP酶活性和AMPK蛋白表达降低,p-AMPK蛋白表达增加。海马区的氧化损伤很明显，小鼠延髓和N2a细胞，PGC-1α和Na+-K+-ATPase蛋白表达明显下调。因此,有理由相信TMT引起的神经毒性症状和能量代谢抑制可能与海马和延髓中p-AMPK和PGC-1α的下调有关。
